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CCR6–CCL20-Mediated Immunologic Pathways in Inflammatory Bowel

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CCR6–CCL20-Mediated Immunologic Pathways in Inflammatory Bowel Review CCR6–CCL20-Mediated Immunologic Pathways in Inflammatory Bowel Disease Ranmali Ranasinghe and Rajaraman Eri * School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, TAS 7250, Australia; [email protected] * Correspondence: [email protected] or [email protected]; Tel.: +61-3-6324-5467 or +61-4-3002-9656; Fax: +61-3-6324-5555 Received: 17 July 2018; Accepted: 19 August 2018; Published: 21 August 2018 Abstract: Inflammatory bowel disease (IBD) has evoked significant interest in human immunobiology given its tactical immune evasion methodologies resulting in acute immune destabilization. IBD comprising Crohn’s disease and Ulcerative colitis manifests as chronic inflammation in the gut mucosa, leading to complexities involving immune dysregulation in the T helper lymphocyte arm, effecting disease pathogenicity. The mucosa of the alimentary canal is constantly exposed to a myriad of food antigens and luminal microorganisms for which a consistent host-protective mechanism is operative in healthy people. Lowered mucosal immune expression which allows penetration of the epithelial barrier by infective pathogenic microbes elicits both innate and adaptive immune responses in the gut, culminating in aberrant intestinal inflammation. Interestingly, the IBD leukocyte repertoire is significantly entwined with chemokine-assisted chemotactic navigation into the sites of inflammation, which is also thought to generate favorable immune-suppressive responses. The functions of the cognate chemokine receptor, CCR6, which binds with its unique ligand CCL20, are expected to tilt the balance between upregulation of homeostatic tolerance and inflammatory pathophysiology. This review aims to critically examine the CCR6-driven immune pathways: TH1/TH2, TH1/TH17, TH17/Treg, IL-23/IL-17, Akt/ERK-1/2, ILC3, and TH9/TH2 for systematic investigation of its underlying mechanisms in the future and to underpin its importance in resolving IBD pathology. Thus, CCR6 occupies an exclusive position in gut immunology which renders it an invaluable therapeutic tool for the production of novel medicaments to treat IBD. Keywords: CCR6; CCL20; TH17 cells; regulatory Treg cells; Inflammatory Bowel Disease; immunologic pathways 1. Introduction Immune-compromised diseases of the gastrointestinal tract have been a topic which has attracted active interest for decades and is one that continues to test the robustness of our immune system. Among the many disease-related models of human immune inactivation, IBD has been a pertinent system within the gut mucosal biology. Importantly, a new immune concept involving the chemokine receptor 6 is gaining momentum with chemokine-activated immune mechanisms coming to the fore. Chemokines are a superfamily of immune-modulatory small protein molecules, which regulate leukocyte migration to inflammatory sites through their chemoattractant properties. Among a plethora of functions, chemotactic navigation of effector T helper cell cohorts to the gut mucosa from lymphatics appears to be primarily a CCR6-driven mechanism, which synchronizes immune homeostasis during IBD pathophysiology. The CCR6–CCL20 axis is a prominent immune modulator in both innate and adaptive immune responses of a wide range of inflammatory diseases. It is associated with tissue Gastrointest. Disord. 2019, 1, 15–29; doi:10.3390/gidisord1010003 www.mdpi.com/journal/gastrointestdisord Gastrointest. Disord. 2019, 1 16 damage and injury, human immunodeficiency virus (HIV), ophthalmic disorders, lung and kidney disorders, autoimmune diseases, brain disease, arthrosclerosis, obesity, diabetes, and cancer [1]. 2. Chemokines Chemokines are a specific group of cytokines that are small molecular proteins known to perform several different functions in the human immune system. Salient functions include T helper lymphocyte differentiation and cell chemotaxis aiding cell migration towards inflammatory locations. Other functions of chemokines are angiogenesis, development of embryos, B cell maturation and differentiation, lymphatic organogenesis, wound healing, inflammation, and cancer metastasis. Chemokines preferentially aid leukocyte homeostasis by directing cell movement towards sites of injury and have been referred to as a specific cell navigational mechanism positioned within the immune system. The total chemokine repertoire consists of 50 chemokines and they belong to receptor and ligand cohorts. Chemokines consists of four subgroups named XC, CX3C, CXC, and CC, in which the naming is based on their receptors. A receptor is denoted by R, and therefore, CC chemokines bind with CCR chemokine receptors. Chemokines display a common molecular structure of having three beta-pleated sheets with an alpha helix at the carbon terminal in which the cysteine motifs are joined by disulfide bonds. The entire chemokine is composed of 67–127 amino acid residues. Chemokine receptors are exhibited on the cell surface and they are described as seven transmembrane domains joined to guanine nucleotide-coupled G1 class protein receptors. One chemokine receptor can bind with many ligands, several ligands can bind with one receptor, or simply, one receptor would bind with one sole ligand. In the case of chemokine receptor 6, it has only one monogamous partner, the chemokine ligand CCL20. Chemokines play a prominent role in inflammation and the spreading of cancer, and interestingly, chemokine inhibition has yielded anti-inflammatory attributes in inflammatory disorders [1]. Chemokine Receptor 6 (CCR6) and Chemokine Ligand CCL20 CCR6 is denoted by a string of different molecular identities, such as: CD196, CKRL3, GPR29, CKR-L3, CMKBR6, GPRCY4, STRL22, BN-1, DCR2, DRY6, CCR-6, and CC-CKR-6 or C-C CKR-6. CCR6 is said to transduce signals that mobilize intracellular calcium ion flux upon binding to its ligand, CCL20. Apart from CCL20, human beta defensins (HBD), which are a group of microbicidal peptides, have been identified as additional epitopes, although this needs thorough validation. Yet, there is increasing evidence that the counterpart of the CCL20 ligand, human beta defensin-2 (HBD2), concomitantly contributes to epithelial cell migration in maintaining intestinal epithelial barrier integrity, and as such, acts as a frontline defense against microbial invasion. Vongsa et al. in 2009 [2] reported equipotent functionality of HBD2 to CCL20, demonstrating that it stimulates active migration of the human intestinal cell lines Caco2, T84, and non-transformed IEC6 ex vivo. It further confirmed that HBD2 is capable of stimulating intracellular calcium influx, which innervates phosphoinositide 3-kinase signal transduction via mobilizing the guanosine triphosphatase (GTPase), RhoA, and phosphorylated myosin light chain, leading to F-actin accumulation, thus shedding light on a possible canonical wound healing mechanism. Therefore, HBD is thought to augment immune cell patrolling, microbial defense, and intestinal barrier restitution. These results significantly underpin the notion that HBD2 parallels the functions of CCL20 in its role as an additional partnering ligand of CCR6. CCL20 was recognized as the principal ligand through calcium ion flux experiments in a K562 cell line devoid of other chemokine receptors but transfected with CCR6. CCL20 has other synonyms, such as LARC (liver and activation-regulated chemokine), MIP-3α (macrophage inflammatory protein), and Exodus-1. CCR6 is predominantly expressed in the appendix, pancreas, lymph nodes, and spleen, with lesser expression in the fetal liver, testis, colon, small intestine, and thymus. Expression of CCL20 is upregulated by intestinal enterocytes responsive to bacteria displaying flagellar movement as well as antigen-presenting dendritic and macrophage subsets, Langerhans cells in the skin, endothelial cells, Gastrointest. Disord. 2019, 1 17 natural killer (NK cells), neutrophils, B cells, and TH17 cells. CCR6 is signatory on the T lymphocyte subdivisions of TH17 and Treg cells, innate lymphoid cells (ILC)-3, neutrophils, NK T cells, B cells, and immature dendritic cells. Distinctively, CCR6 is thought to trigger the PI3 kinase (phosphoinositide 3 kinase) signal transduction cascade, which leads to phosphorylation that provides energy for cell chemotaxis [1,2]. 3. Importance of IBD IBD consists of an immune-compromised disease complex that includes two sub phenotypes: Crohn’s disease (CD) and Ulcerative colitis (UC), characterized by chronic inflammation within the intestine. These are multifactorial, heritable diseases, which have more than 200 single nucleotide polymorphisms (SNP), including NOD2, ATR16GL, XBPI, IL23R, STAT3, JAK2 and CCR6, that sometimes manifest in genetically predisposed individuals [3]. Recently, heritability was endowed with only 25% probability for being recognized as the cardinal factor causing disease because a multitude of environmental factors are also now held accountable [4]. Fifty percent concordance of CD in monozygotic twins, rising incidence of disease in the past 60 years without changes in the genetic makeup, lower rates of IBD in underdeveloped countries, and development of IBD in immigrants to countries of high prevalence have all emphasized the importance of multiple environmental influences on the inception of the disease [5]. Rather than blaming it all on genetic predisposition and the microbiome, the trend now is to focus on new signaling pathways: one of these is the ER-stress-induced apoptosis due to the unfolded protein response, resulting in the autophagy
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